Synthetic methods for the generation of enantioenriched quaternary stereocenters are highly desirable given their prevalence as motifs in a wide variety of biologically active molecules of both natural and unnatural origin, and the pharmaceutical industries increasing recognition for the motif's applicability in drug design. Despite their importance, the number of highly enantioselective transformations that construct quaternary stereocenters under mild reaction conditions is limited, with respect to both cyclic and acyclic systems.
Since 1965, transition metal-catalyzed allylic alkylation has emerged as one of the most powerful methods for the construction of stereocenters. In particular, with the use of prochiral nucleophiles that proceed through tetrasubstituted enolates, the transition metal-catalyzed enantioselective allylic alkylation has proven to be a formidable strategy for accessing chiral quaternary stereocenters in catalytic enantioselective fashion. Although this transformation has been studied for more than 50 years, the use of α-substituted lactones or lactams as prochiral nucleophiles remains significantly under-developed.
It is particularly difficult to construct quaternary stereocenters in scaffolds containing an additional functional handle for further synthetic manipulation, such as α-acyl lactones and lactams. Lactone products could also provide access to acyclic quaternary stereocenters via ring-opening reactions and reduction of the lactam products would enable direct access to functionalized piperidine rings, the most prevalent nitrogenous heterocycle in drug molecules.
Recently, a palladium-catalyzed decarboxylative enantioselective allylic alkylation of enol carbonates derived from γ-butyrolactones was disclosed. Various enol carbonates were used to obtain diverse α-acyl quaternary butyrolactones in moderate to high levels of enantioselectivity. Nonetheless, the limited electrophile scope and challenging nucleophile synthesis limits the practicality of this transformation. In particular, the alkylation appears limited to γ-butyrolactone substrates and an allyl group, and the substrates require low-yielding, multi-step synthesis.
Therefore, the catalytic enantioselective construction of all-carbon quaternary centers represents a considerable challenge in synthetic organic chemistry due to the difficulties associated with effecting an enantioselective C—C bond formation in a sterically hindered environment.
Accordingly, there is a need to develop new reaction protocols that provide access to cyclic and acyclic α-quaternary carboxylic acid derivatives (i.e., acids, esters, amides).